Streptozotocin causes neurotoxic effect in cultured cerebellar granule neurons

Генрихс, Е. Е.; Stelmashook, E. V.; Golyshev, Sergey A.; Aleksandrova, O. P.; Isaev, N. K.

doi:10.1016/j.brainresbull.2017.01.004

Cited by 16 publications

(12 citation statements)

References 22 publications

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“…In primary cell cultures, however, slightly higher concentrations of STZ were found to exert similar damage. In rat cerebellar granule cells, significant cell damage was induced by 2.5-4.5 mM (Genrikhs et al 2017) and 3-4 mM STZ (Isaev et al 2018), while the proliferation of adult hippocampal neural stem cells (NSCs) was inhibited by 2.5 mM STZ (Sun et al 2018). These concentrations correspond well to the 4 Insulin dose and time dependently improved plasma membrane integrity in LS-and 1 mM STZ-treated cells.…”

Section: Discussionmentioning

confidence: 69%

“…Reduced IRS-1 expression was also observed in SH-SY5Y cells treated by 0.8 mM STZ (Wang et al 2011) and decreased GSK-3 phosphorylation was found in SK-N-MC cells after 1 mM STZ treatment (Plaschke and Kopitz 2015). Cytoprotective effect of insulin against STZ induced toxicity was also reported in cerebellar granule cells (Genrikhs et al 2017). These results collectively suggest that STZ treatment interferes with glucose and insulin metabolism in neuronal cells; however, the development of insulin resistance was not unequivocally proven so far.…”

Section: Discussionmentioning

confidence: 76%

“…STZ is also used in in vitro experiments aiming at modeling cellular processes characteristic for Alzheimer's disease and its potential therapeutic measures (Plaschke and Kopitz 2015;Rajasekar et al 2016;Guo et al 2016). STZ exerted dose-dependent cytotoxicity on several neuronal cell types (Plaschke and Kopitz 2015;Isaev et al 2018;Genrikhs et al 2017) leading to depolarization of mitochondrial membrane (Genrikhs et al 2017;Biswas et al 2017), oxidative stress (Rajasekar et al 2014), increased apoptosis (Rajasekar et al 2014;Biswas et al 2016Biswas et al , 2017, increased tau protein phosphorylation (Biswas et al 2016), decreased glucose uptake (Biswas et al 2016(Biswas et al , 2017 and expression of GLUTs (Biswas et al 2017;Sun et al 2018), reduced expression of insulin receptor substrate-1 (IRS-1) (Wang et al 2011), and decreased levels of phosphorylated GSK-3 (Plaschke and Kopitz 2015;Rajasekar et al 2014). The protective effect of insulin against STZ-induced impaired cell viability was observed as well (Genrikhs et al 2017;Rajasekar et al 2014).…”

Section: Introductionmentioning

confidence: 99%

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Lack of insulin resistance in response to streptozotocin treatment in neuronal SH-SY5Y cell line

Bagaméry

Kecsmár

et al. 2019

J Neural Transm

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Recently, it is suggested that brain insulin resistance may contribute to the development of Alzheimer's disease; therefore, there is a high interest in its investigation. Streptozotocin (STZ) is often used to induce dysregulation of glucose and insulin metabolism in animal and cell culture models. Alteration in insulin sensitivity however, has not yet been assessed in neuronal cells after STZ treatment. We aimed at studying the concentration dependence of the protective effect of insulin on STZ-induced damage using SH-SY5Y cell line. Cells were treated with STZ and cell viability was assessed by resazurin reduction and lactate dehydrogenase release assays. Low serum (LS) medium was used as control damage. The effect of various concentrations (30, 100, 300, 1000 nM) of insulin was studied on cell viability and glycogen synthase kinase-3 (GSK-3) phosphorylation, an indicator of insulin signaling. STZ induced dose-and time-dependent cytotoxicity, its 1 mM concentration exerted a low, gradually developing damage. The cytoprotective effect of insulin was demonstrated in both STZ and LS groups. Its maximal effect was lower in the STZ-treated cells; however, its effective concentration remained largely unaltered. Insulin-induced GSK-3 phosphorylation was similar in the STZ-and LS-treated cells suggesting unchanged insulin signaling. Our present results indicate that STZ does not induce significant impairment in insulin sensitivity in SH-SY5Y cells, thus in this cell line it is not a good tool for studying the role of insulin resistance in neurodegeneration and to examine protective agents acting by improving insulin signaling.

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Lack of insulin resistance in response to streptozotocin treatment in neuronal SH-SY5Y cell line

Bagaméry

Kecsmár

et al. 2019

J Neural Transm

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“…Since other studies have shown attenuated photoreceptor function in ex vivo transretinal recordings from STZ mice, 40 our findings may be model dependent, or restricted to the type 2 diabetic db/db mouse. It is also possible that compromised rod photoreceptor function in the STZ mouse model derives from neurotoxic effects of STZ 41 rather than a consequence of diabetes. Our results are consistent with other ex vivo studies showing reduced inhibitory output from amacrine cells but no changes in excitatory output of rods and increased or unaltered ON bipolar cell output in diabetic retinas.…”

Section: Discussionmentioning

confidence: 99%

Rod phototransduction and light signal transmission during type 2 diabetes

Becker

Carroll

Vinberg

2020

BMJ Open Diab Res Care

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IntroductionDiabetic retinopathy is a major complication of diabetes recently associated with compromised photoreceptor function. Multiple stressors in diabetes, such as hyperglycemia, oxidative stress and inflammatory factors, have been identified, but systemic effects of diabetes on outer retina function are incompletely understood. We assessed photoreceptor physiology in vivo and in isolated retinas to better understand how alterations in the cellular environment compared with intrinsic cellular/molecular properties of the photoreceptors, affect light signal transduction and transmission in the retina in chronic type 2 diabetes.Research design and methodsPhotoreceptor function was assessed in BKS.Cs-Dock7m+/+Lepr db/J mice, using homozygotes for Leprdb as a model of type 2 diabetes and heterozygotes as non-diabetic controls. In vivo electroretinogram (ERG) was recorded in dark-adapted mice at both 3 and 6 months of age. For ex vivo ERG, isolated retinas were superfused with oxygenated Ames’ media supplemented with 30 mM glucose or mannitol as iso-osmotic control and electrical responses to light stimuli were recorded.ResultsWe found that both transduction and transmission of light signals by rod photoreceptors were compromised in 6-month-old (n=9–10 eyes from 5 animals, ***p<0.001) but not in 3-month-old diabetic mice in vivo (n=4–8 eyes from 2 to 4 animals). In contrast, rod signaling was similar in isolated retinas from 6-month-old control and diabetic mice under normoglycemic conditions (n=11). Acutely elevated glucose ex vivo increased light-evoked rod photoreceptor responses in control mice (n=11, ***p<0.001), but did not affect light responses in diabetic mice (n=11).ConclusionsOur data suggest that long-term diabetes does not irreversibly change the ability of rod photoreceptors to transduce and mediate light signals. However, type 2 diabetes appears to induce adaptational changes in the rods that render them less sensitive to increased availability of glucose.

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“…Since other studies have shown attenuated photoreceptor function in ex vivo transretinal recordings from STZ mice (36), our findings may not be universal and restricted to the db/db mouse as a model of type 2 diabetes. It is also possible that compromised rod photoreceptor function in the STZ mouse model is due to known neurotoxic effects of STZ (37) rather than a consequence of diabetes. Consistent with a recent study by Calbiague et al , we also did not find evidence for impaired ON bipolar cell function in diabetic retinas ex vivo (38) .…”

Section: Discussionmentioning

confidence: 99%

Rod phototransduction and light signal transmission during type 2 diabetes

Becker

Vinberg

2020

Preprint

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Diabetic retinopathy is a major complication of diabetes recently associated with attenuated photoreceptor function. Multiple stressors in diabetes, such as hyperglycemia, oxidative stress and inflammatory factors, have been identified, but systemic effects of diabetes on outer retina function are incompletely understood. Ex vivo ERG presents the unique opportunity to test rod photoreceptor light signal transduction and transmission and determine whether they are permanently compromised and/or adapt to hyperglycemia in chronic type 2 diabetes. Lightevoked rod photoreceptor signals in control and diabetic mice in vivo were compared to those recorded ex vivo under normal or elevated extracellular glucose. Transduction and transmission of light signals were compromised in 6 mo. diabetic mice in vivo. In contrast, ex vivo rod signaling was similar in isolated retinas from 6 mo. control and diabetic mice under normoglycemic conditions. Acutely elevated glucose ex vivo increased light-evoked photoreceptor responses in control mice, but did not affect light responses in diabetic mice. In summary, our data suggest that long-term diabetes does not irreversibly change the ability of rod photoreceptors to transduce and mediate light signals. However, type 2 diabetes appears to induce adaptational changes in the rods that render them less sensitive to increased availability of glucose.Diabetic retinopathy, one of the leading causes of irreversible vision loss worldwide (1), has traditionally been characterized by retinal vascular abnormalities. Recent studies in human patients with diabetes suggest, however, that retinal diabetic neuropathy with neuroglial dysfunction and degeneration frequently precedes visible microvasculopathy (2-4). Even in the absence of or with minimal signs of retinal vascular abnormalities, patients with diabetes show dysfunction and loss of retinal neuronal cells. In fact, impairment of the neurovascular unit has been suggested to lead to or accelerate retinal vascular disease progression, since implicit time delay of the multifocal electroretinogram (ERG) predicts onset of visible vascular changes (5). Damage to nerve fiber, ganglion cell and inner plexiform layers in the human eye has been demonstrated in diabetes by impaired pattern ERG and oscillatory potentials (6) and thinning of inner retinal layers (4). Reduced amplitudes and longer implicit times of the scotopic and photopic b-waves (6) also implicate dysfunction of rod and cone bipolar cells in retinal diabetic neuropathy of human patients. These findings are not universal, however, and reduced scotopic a-and b-wave amplitudes have not been shown in all studies (7). Murine models of diabetes share many features of retinal dysfunction and cell loss with those in patients with diabetes. The positive component of the scotopic threshold response, as a measure of retinal ganglion cell function, is attenuated (8) and nerve fiber and ganglion cell layer thickness and retinal ganglion cell density are reduced (4) in streptozotocin (STZ)-induced di...

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Streptozotocin causes neurotoxic effect in cultured cerebellar granule neurons

Cited by 16 publications

References 22 publications

Lack of insulin resistance in response to streptozotocin treatment in neuronal SH-SY5Y cell line

Lack of insulin resistance in response to streptozotocin treatment in neuronal SH-SY5Y cell line

Rod phototransduction and light signal transmission during type 2 diabetes

Rod phototransduction and light signal transmission during type 2 diabetes

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